Impaired β-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose

被引:144
作者
Marshak, S
Leibowitz, G
Bertuzzi, F
Socci, C
Kaiser, N
Gross, DJ
Cerasi, E
Melloul, D
机构
[1] Hadassah Univ Hosp, Dept Endocrinol & Metab, IL-91120 Jerusalem, Israel
[2] Univ Milan, Ist Sci San Raffaele, Milan, Italy
[3] Univ Milan, Cattedra Patol Chirurg, Milan, Italy
关键词
D O I
10.2337/diabetes.48.6.1230
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
In type 2 diabetes, chronic hyperglycemia has been suggested to be detrimental to beta-cell function, causing reduced glucose-stimulated insulin secretion and disproportionately elevated proinsulin. In the present study, we investigated the effect on several beta-cell functions of prolonged in vitro exposure of human pancreatic islet cultures to high glucose concentrations. Islets exposed to high glucose levels (33 mmol/l) for 4 and 9 days showed dramatic decreases in glucose-induced insulin release and in islet insulin content, with increased proportion of proinsulin-like peptides relative to insulin. The depletion in insulin stores correlated with the reduction in insulin mRNA levels and human insulin promoter transcriptional activity. We also demonstrated that high glucose dramatically lowered the binding activity of pancreatic duodenal homeobox 1 (the glucose-sensitive transcription factor), whereas the transcription factor rat insulin promoter element 3b1 activator was less influenced and insulin enhancer factor 1 remained unaffected. Most of these p-cell impairments mere partially reversible when islets first incubated for 6 days in high glucose were transferred to normal glucose (5.5 mmol/l) concentrations for 3 days. We conclude that cultured human islets are sensitive to the deleterious effect of high glucose concentrations at multiple functional levels, and that such mechanisms may play an important role in the decreased insulin production and secretion of type 2 diabetic patients.
引用
收藏
页码:1230 / 1236
页数:7
相关论文
共 47 条
[1]  
ALARCON C, 1993, J BIOL CHEM, V268, P4276
[2]   INCREASED SECRETORY DEMAND RATHER THAN A DEFECT IN THE PROINSULIN CONVERSION MECHANISM CAUSES HYPERPROINSULINEMIA IN A GLUCOSE-INFUSION RAT MODEL OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS [J].
ALARCON, C ;
LEAHY, JL ;
SCHUPPIN, GT ;
RHODES, CJ .
JOURNAL OF CLINICAL INVESTIGATION, 1995, 95 (03) :1032-1039
[3]  
[Anonymous], 1996, Diabetes Rev
[4]  
Bertuzzi F, 1995, TRANSPLANT P, V27, P3243
[5]   Effects of prolonged glucose infusion on insulin secretion, clearance, and action in normal subjects [J].
Boden, G ;
Ruiz, J ;
Kim, CJ ;
Chen, XH .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 1996, 270 (02) :E251-E258
[6]   ABNORMAL SENSITIVITY TO GLUCOSE OF HUMAN ISLETS CULTURED IN A HIGH GLUCOSE MEDIUM - PARTIAL REVERSIBILITY AFTER AN ADDITIONAL CULTURE IN A NORMAL GLUCOSE MEDIUM [J].
DAVALLI, AM ;
RICORDI, C ;
SOCCI, C ;
BRAGHI, S ;
BERTUZZI, F ;
FATTOR, B ;
DICARLO, V ;
PONTIROLI, AE ;
POZZA, G .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1991, 72 (01) :202-208
[7]   PROLONGED EXPOSURE OF PANCREATIC-ISLETS ISOLATED FROM PREDIABETIC NONOBESE DIABETIC MICE TO A HIGH GLUCOSE-CONCENTRATION DOES NOT IMPAIR BETA-CELL FUNCTION [J].
EIZIRIK, DL ;
STRANDELL, E ;
SANDLER, S .
DIABETOLOGIA, 1991, 34 (01) :6-11
[8]   PROLONGED EXPOSURE OF HUMAN PANCREATIC-ISLETS TO HIGH GLUCOSE-CONCENTRATIONS INVITRO IMPAIRS THE BETA-CELL FUNCTION [J].
EIZIRIK, DL ;
KORBUTT, GS ;
HELLERSTROM, C .
JOURNAL OF CLINICAL INVESTIGATION, 1992, 90 (04) :1263-1268
[9]  
FLATT PR, 1994, INSULIN SECRETION PA, P481
[10]   HYPERPROINSULINEMIA IN THE DIABETIC PSAMMOMYS-OBESUS IS A RESULT OF INCREASED SECRETORY DEMAND ON THE BETA-CELL [J].
GADOT, M ;
ARIAV, Y ;
CERASI, E ;
KAISER, N ;
GROSS, DJ .
ENDOCRINOLOGY, 1995, 136 (10) :4218-4223